It is an object of this invention to provide novel compounds having potent analgesic properties similar to morphine, but with only slight addiction potential similar to the potent narcotic antagonist, N-allylnormorphine (Nalline).
Many N-alkyl analogs of norcodeine and normorphine are known, see, for example, R. L. Clark, A. A. Pessolano, J. Weijlard and K. Pfister, 3rd, Am. Chem. Soc. J., 75, 4963-4966, (1953).
Previous exploration has concerned the N-primary alkyl analogs of norcodeine and normorphine. These N-alkyl analogs have not found clinical acceptance either because they lack the required potency or were considered to have excessive potential for addiction liability.
It has been taught in the work of Archer, et al., J. Med. Chem., 7, 123-127 (1964) that compounds possessing potent analgesic properties along with a degree of antagonist activity are useful analgesics in the clinic, usually having far less addiction potential than pure agonist compounds. Such an example is the clinically useful drug, pentazocine, a dual agonist-antagonist with an analgesic potency about one-fourth that of morphine.
The present invention provides novel N-sec-alkyl analogs of norcodeine and normorphine which have potent analgesic and antagonist qualities. The only known N-sec-alkyl norcodeine and normorphine analogs are the N-isopropyl-norcodeine and N-isopropyl-normorphine compounds which are taught in the Clark et al. paper. However, as reported by co-workers of Clark et al. who performed the pharmacological testing, the N-isopropyl-normorphine compound was not a good agonist and had little, if any, antagonist qualities. The N-isopropyl-norcodeine was, of course, inactive. See Charles A. Winter, Peter D. Orahovats and Edward G. Lehman, Arch. int. Pharmacodyn, CX, No. 2-3, 186-202, (1957).
While some N-alkylnormorphines (such as N-butyl-, N-amyl-, or N-hexylnormorphine) have potent analgesic activity, they are devoid of antagonist properties. See Clark et al. paper. On the other hand, N-primary loweralkyl normorphines such as N-propyl normorphine and N-isobutylnormorphine have been shown to be morphine antagonists only. See U.S. Pat. No. 2,741,609 to John Weijlard and U.S. Pat. No. 2,741,614 to Robert L. Clark, as well as the data presented herein for N-propylnormorphine.
We have found that N-2-butyl, N-3-phenyl, N-.alpha.-methylallyl and N-.alpha.-methylcyclopropylmethyl derivatives of normorphine, together with the acid salts thereof possess analgesic activities similar to morphine while at the same time displaying antagonist properties indicative of low addiction potential. These results are particularly surprising in view of the fact that other N-lower alkylnormorphines do not demonstrate this mixed agonist-antagonist activity with the expected useful range of analgesic potency.